Abstract
Reactive oxygen and nitrogen species are important microbicidal agents and are also involved in lymphocyte unresponsiveness during experimental infections. Many of the biological effects attributed to nitric oxide are mediated by peroxynitrites, which induce the nitration of immune cells, among others. Our group has demonstrated that nitric oxide is involved in the suppressive activity of myeloid-derived suppressor cells in Trypanosoma cruzi-infected mice, with a higher number of CD8+ T cells suffering surface-nitration compared to uninfected controls. Studying the functional and phenotypic features of peripheral CD8+ T cells from chagasic patients and human cells experimentally infected with T. cruzi, we found that different regulatory mechanisms impaired the effector functions of T cytotoxic population from seropositive patients. Peripheral leukocytes from chagasic patients showed increased nitric oxide production concomitant with increased tyrosine nitration of CD8+ T cells. Additionally, this cytotoxic population exhibited increased apoptotic rate, loss of the TCRζ-chain, and lower levels of CD107a, a marker of degranulation. Strikingly, IL-6 stimulation of in vitro-infected peripheral blood mononuclear cells obtained from healthy donors, blunted T. cruzi-induced nitration of CD3+CD8+ cells, and increased their survival. Furthermore, the treatment of these cultures with an IL-6 neutralizing antibody increased the percentage of T. cruzi-induced CD8+ T cell nitration and raised the release of nitric oxide. The results suggest that the under-responsiveness of cytotoxic T cell population observed in the setting of long-term constant activation of the immune system could be reverted by the pleiotropic actions of IL-6, since this cytokine improves its survival and effector functions.
Highlights
CD8+ T cells play a critical role in the immunity against intracellular pathogens, including the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas cardiomyopathy [1]
A total of 46 peripheral blood samples from chagasic and non-chagasic donors of both sexes, collected from people living in Cordoba (Argentina) were analyzed for T. cruzi-specific antibodies by enzyme-linked immunosorbent assay (ELISA) and indirect hemagglutination (IHA) (Table 1)
Multiple immunological effector mechanisms are critical for resolving T. cruzi infection, but considering that this parasite invades and replicates in essentially all types of mammalian cells, T cells and monocytes/macrophages are important for controlling the infection
Summary
CD8+ T cells play a critical role in the immunity against intracellular pathogens, including the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas cardiomyopathy [1]. Chagas disease is characterized by two distinct phases: the acute phase, which lasts several weeks and is characterized by non-specific symptoms; and the chronic phase, lasting lifelong. The host’s ability to control T. cruzi infection is substantial, but not fully effective, since most infected individuals tightly. Up to 40% of infected individuals develop progressive heart disease leading to an end-stage dilated cardiomyopathy. One key defense mechanism against T. cruzi is exerted by nitric oxide (NO), which is produced by inducible NO synthase, among other enzymes, present in monocytes/macrophages and cardiomyocytes [4, 5]. The parasite triggers activation of macrophage NADPH oxidase, resulting in a continuous pro-
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